Chronic rhinosinusitis (CRS) is one of the most frequently reported chronic diseases in the U.S. Even with aggressive medical and surgical therapies, many CRS patients have persistent disease. The pathogenesis of CRS is not well understood, and the current treatment regimens for CRS are aimed at alleviating symptoms. The clinical relationship between CRS and asthma is an increasing health concern. Thus, the long-term goal of this grant project is to understand the pathophysiologic mechanisms of CRS. Persistent inflammation, eosinophilia and increased numbers of T cells producing Th2-type cytokines are commonly seen in the sinus mucosa of CRS patients in the U.S. and Europe. Major questions still remain: 1) how do CRS patients develop Th2-type airway inflammation, and 2) why is such Th2-type airway inflammation prolonged and/or exacerbated over time? We now hypothesize that CRS is mediated by dysregulated airway mucosal responses to environmental insults, specifically increased production of the molecules associated with cell injury or stress, namely IL-33 and tissue uric acid. In this project, we will test the hypothesis tat increased and prolonged production of IL-33 in the airway in response to environmental insults, such as viruses, allergens, bacteria and fungi, induces Th2-type airway inflammation in sinonasal mucosa, which is further aggravated by an auto-inflammatory mechanism involving endogenous uric acid. We will test this hypothesis by focusing on two independent but integrated aims. In Aim 1, we will investigate the cause-effect relationship between production and/or release of IL-33 and tissue uric acid and chronic airway inflammation in mouse models. By using transgenic and gene- deficient mice, antibodies, and pharmacological approaches, we will dissect the cause-effect relationships among IL-33, uric acid and chronic Th2-type airway inflammation. In Aim 2, we will investigate whether IL-33 and tissue uric acid are involved in exacerbation of upper airway inflammation and worsening of clinical symptoms in patients with CRS. We will test the hypothesis that the natural disease exacerbation occurring in patients with CRS during the winter season is mediated by respiratory virus infection and subsequent prolonged production and/or release of IL-33 and uric acid in the airways. This study aims to provide a renewed understanding of the pathophysiology of CRS by focusing on endogenous proinflammatory factors (i.e. IL-33, uric acid). We have all the necessary research tools already in place for Aim 1, and the P.I. and co-investigators are familiar with and highly committed to accomplishing the prospective clinical study in Aim 2. Successful completion of this project will provide novel conceptual advances in our understanding of the pathophysiology of CRS and will provide new treatment and preventive strategies for this common, costly, and incapacitating disorder. Because CRS and asthma often co-exist, new concepts derived from this project will have a high impact on the fields of both CRS and asthma.